ITMI20011240A1 - DRUGS FOR VASCULOPATHIES - Google Patents

DRUGS FOR VASCULOPATHIES Download PDF

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Publication number
ITMI20011240A1
ITMI20011240A1 IT2001MI001240A ITMI20011240A ITMI20011240A1 IT MI20011240 A1 ITMI20011240 A1 IT MI20011240A1 IT 2001MI001240 A IT2001MI001240 A IT 2001MI001240A IT MI20011240 A ITMI20011240 A IT MI20011240A IT MI20011240 A1 ITMI20011240 A1 IT MI20011240A1
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Prior art keywords
acid
nitroxymethyl
benzoic acid
acetyloxy
ester
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IT2001MI001240A
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Italian (it)
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Soldato Piero Del
Original Assignee
Nicox Sa
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Priority to IT2001MI001240A priority Critical patent/ITMI20011240A1/en
Publication of ITMI20011240A0 publication Critical patent/ITMI20011240A0/en
Priority to PCT/EP2002/005846 priority patent/WO2002100400A1/en
Priority to US10/479,978 priority patent/US20040171592A1/en
Priority to EP02747327A priority patent/EP1406613B1/en
Priority to ES02747327T priority patent/ES2296964T3/en
Priority to JP2003503221A priority patent/JP2004533462A/en
Priority to DE60223810T priority patent/DE60223810T2/en
Publication of ITMI20011240A1 publication Critical patent/ITMI20011240A1/en

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
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    • A61P9/08—Vasodilators for multiple indications
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A—HUMAN NECESSITIES
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Description

Descrizione dell ' invenzione industriale : Description of the industrial invention:

La presente invenzione riguarda l'uso di farmaci nella prevenzione e/o trattamento delle vasculopatie. The present invention relates to the use of drugs in the prevention and / or treatment of vasculopathies.

Le patologie cardiovascolari più severe (fra cui trombosi, restenosi, stroke, aterosclerosi, infarto miocardico, malattie vascolari periferiche e centrali, etc.) sono caratterizzate da un'attivazione patologica di cellule vascolari (cellule della muscolatura liscia vasale, cellule endoteliali) ed ematiche (piastrine, leucociti, monociti/macrofagi, etc.). The most severe cardiovascular diseases (including thrombosis, restenosis, stroke, atherosclerosis, myocardial infarction, peripheral and central vascular diseases, etc.) are characterized by a pathological activation of vascular cells (vascular smooth muscle cells, endothelial cells) and blood cells (platelets, leukocytes, monocytes / macrophages, etc.).

Le vasculopatie e le malattie ad esse associate sono condizioni patologiche accompagnate da un alterato quadro ematochimico e clinico, che si manifesta con iperglicemia e/o iperinsulinemia, iperlipidemia e/o ritenzione idrica-salina e/o iperproliferazione di cellule vasali e/o tumorali, e/o attività protrombotica e procoagulante, etc. Le vasculopatie possono facilitare l'insorgenza di altre patologie quali obesità, diabete e malattie cardiovascolari quali ad esempio ischemie miocardiche, cerebrali e/o periferiche, retinopatie, polineuropatie, gastroenteropatie, nefropatie, etc., ipertensione (generale e regionale a livello polmonare, coronario, portale, renale, etc.), aterosclerosi, malattia di Alzheimer, cancro. Vasculopathies and associated diseases are pathological conditions accompanied by an altered blood chemistry and clinical picture, which manifests itself with hyperglycemia and / or hyperinsulinemia, hyperlipidemia and / or water-saline retention and / or hyperproliferation of vascular and / or tumor cells, and / or prothrombotic and procoagulant activity, etc. Vasculopathies can facilitate the onset of other pathologies such as obesity, diabetes and cardiovascular diseases such as myocardial, cerebral and / or peripheral ischemias, retinopathies, polyneuropathies, gastroenteropathies, nephropathies, etc., hypertension (general and regional at the pulmonary, coronary level , portal, renal, etc.), atherosclerosis, Alzheimer's disease, cancer.

Nelle vasculopatie sono conprese anche patologie particolari quali la sindrome X (o resistenza insulinica) e la vasculopatia da farmaci. Particular pathologies such as syndrome X (or insulin resistance) and drug-induced vasculopathy are also included in vascular disease.

Non esiste un approccio terapeutico unitario che sia in grado di prevenire e/o ridurre le vasculopatie. There is no single therapeutic approach that is able to prevent and / or reduce vascular disease.

L'approccio ideale è quello di intervenire sui diversi processi cellulari, e cioè di prevenire l'attivazione patologica delle suddette cellule, che porta all'instaurarsi ed al progredire del processo patologico a carico del sistema cardiovascolare. The ideal approach is to intervene on the different cellular processes, that is to prevent the pathological activation of the aforementioned cells, which leads to the establishment and progress of the pathological process affecting the cardiovascular system.

Attualmente i farmaci utilizzati per le vasculopatie e gli approcci terapeutici utilizzati inibiscono una sola popolazione cellulare, quindi agiscono solo su una fase del processo, con risultati solo parzialmente soddisfacenti. Currently the drugs used for vasculopathies and the therapeutic approaches used inhibit a single cell population, therefore they act only on one phase of the process, with only partially satisfactory results.

Le statine, la rapamicina e il trattamento radioterapico hanno effetti solo sulla muscolatura liscia ma non sulle altre popolazioni cellulari. I risultati che si ottengono con questi trattamenti farmacologici e con la radioterapia sono solo parzialmente soddisfacenti e pertanto occorre aumentare i dosaggi con conseguenti effetti collaterali anche severi. Statins, rapamycin, and radiation treatment only affect smooth muscle but not other cell populations. The results obtained with these pharmacological treatments and with radiotherapy are only partially satisfactory and therefore it is necessary to increase the dosages with consequent even severe side effects.

Era sentita l'esigenza di disporre di farmaci che consentissero di realizzare un trattamento terapeutico efficace delle vasculopatie, superando gli inconvenienti associati ai trattamenti terapeutici e chirurgici attualmente utilizzati, e che fossero efficaci nell'inibizione dell'attivazione patologica di diverse popolazioni cellulari del sistema cardiovascolare e in più che non risultassero tossici, in particolare a livello gastrico, e inoltre fossero utilizzabili per trattamenti prolungati senza effetti collaterali. The need was felt to have drugs that would allow an effective therapeutic treatment of vascular diseases, overcoming the drawbacks associated with the therapeutic and surgical treatments currently used, and that were effective in inhibiting the pathological activation of different cell populations of the cardiovascular system and in addition that they were not toxic, in particular at the gastric level, and were also usable for prolonged treatments without side effects.

Questo problema tecnico è stato ora risolto dalla Richiedente utilizzando una specifica classe di farmaci. Sorprendentemente e inaspettatamente la Richiedente ha trovato che i nitrossi derivati dell'acido salicilico e suoi derivati sono attivi nel trattamento delle vasculopatie, agendo sui processi cellulari coinvolti. Questo risultato è sorprendente in guanto altri nitroossi derivati, quali ad esempio i derivati di piroxicam e ketorolac, non sono risultati attivi alle dosi non tossiche. Il risultato è ancora più inaspettato se si considera che l'aspirina agisce sulle piastrine, in modo molto parziale sui monociti/macrofagi, ed è inattiva sulle cellule della muscolatura liscia, sui leucociti e sulle cellule endoteliali. This technical problem has now been solved by the Applicant using a specific class of drugs. Surprisingly and unexpectedly, the Applicant has found that the nitroxy derivatives of salicylic acid and its derivatives are active in the treatment of vasculopathies, acting on the cellular processes involved. This result is surprising since other nitroxy derivatives, such as for example the derivatives of piroxicam and ketorolac, were not active at non-toxic doses. The result is even more unexpected if we consider that aspirin acts on platelets, in a very partial way on monocytes / macrophages, and is inactive on smooth muscle cells, leukocytes and endothelial cells.

Costituisce un oggetto della presente invenzione l'uso nelle vasculopatie di composti, o loro sali, aventi la seguenti formula generale: An object of the present invention is the use in vascular disease of compounds, or their salts, having the following general formula:

in cui : in which :

c0 è un intero ed é 0 oppure l; c0 is an integer and is 0 or l;

b0 è un intero ed è 0 oppure l, con la condizione che c0 e b0 non possono essere contemporaneamente uguali a zero. b0 is an integer and is 0 or l, with the proviso that c0 and b0 cannot be equal to zero at the same time.

A = R-C (=0) , in cui A = R-C (= 0), where

R é il radicale del farmaco precursore scelto tra l'acido salicico o acetilsalicilico, R is the radical of the precursor drug chosen from salicic or acetylsalicylic acid,

in cui in which

sono uguali o diversi; they are the same or different;

oppure un alchile lineare o ramificato, avente da l a 5 atomi di carbonio; or a linear or branched alkyl, having from 1 to 5 carbon atoms;

oppure in cui tx e txx hanno il valore di 0 oppure l; con la condizione che tx = l quando txx = 0, tx = 0 quando txx = 1; X é come sopra definito; or in which tx and txx have the value of 0 or l; with the condition that tx = l when txx = 0, tx = 0 when txx = 1; X is as defined above;

X2, radicale bivalente, é tale che il corrispondente precursore di B, in cui la valenza libera di TB è saturata con z, e quella di TBI con OZ, Z oppure con in cui preferibilmente C1-C5 alchile lineare o ramificato quando possibile, Z<I>, Z<II >uguali o diversi hanno i valori di Z come sopra definito, a seconda che X2, divalent radical, is such that the corresponding precursor of B, in which the free valence of TB is saturated with z, and that of TBI with OZ, Z or with which preferably C1-C5 linear or branched alkyl when possible, Z <I>, Z <II> the same or different have the values of Z as defined above, depending on that

oppure X, in funzione dei valori di t, t', tx e txx; il composto precursore di B essendo scelto tra i seguenti: or X, as a function of the values of t, t ', tx and txx; the precursor compound of B being selected from the following:

amminoacidi, scelti tra i seguenti: L-carnosina, anserina, selenocisteina, selenometionina, penicilamina, N-acetilpenicilamina, cisteina, N-acetilcistena, glutatione o suoi esteri, preferibilmente estere etilico o isopropilico,-idrossiacidi, scelti tra i seguenti: acido gallico, acido ferulico, acido gentisico, acido citrico, acido caffeico, diidrocaffeico, acido p-cumarico, acido vanillico; amino acids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicylamine, N-acetylpenicylamine, cysteine, N-acetylcystene, glutathione or its esters, preferably ethyl or isopropyl ester, -hydroxy acids, selected from the following: gallic acid , ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic acid, p-coumaric acid, vanillic acid;

polialcooli aromatici ed eterociclici, scelti tra i seguenti: acido nordiiclroguaiaretico, quercetina, catechina, kaempferolo, sulfuretina, acido ascorbico, acido isoascorbico, idrochinone, gossypol, acido reductico, metossiidrochinone, idrossiidrochinone, propil gallato, saccarosio, 3,5-di-tertbutil-4-idrossibenziltio glicollato, alcool p-cumarico, 4-idrossifeniletilalcool, alcool coniferilico, allopurinolo,-composti contenenti almeno una funzione acida libera, scelti tra i seguenti: acido 3,3'-tiodipropionico, acido fumarico, acido diidrossimaleico, acido edetico; aromatic and heterocyclic polyalcohols, selected from the following: nordiichlroguaiaretic acid, quercetin, catechin, kaempferol, sulfuretin, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxyhydroquinone, hydroxyhydroquinone, propyl gallate, sucrose-3,5 -4-hydroxybenzylthio glycollate, p-coumaric alcohol, 4-hydroxyphenylethyl alcohol, coniferyl alcohol, allopurinol, -compounds containing at least one free acid function, selected from the following: 3,3'-thiodipropionic acid, fumaric acid, dihydroxymal acid, edetic acid ;

C é il radicale bivalente -Tc-Y- in cui C is the divalent radical -Tc-Y- in which

Tc = (CO) quando tx = 0, Tc = X quando txx = 0, essendo X come sopra definito; Tc = (CO) when tx = 0, Tc = X when txx = 0, being X as defined above;

Y é: Y is:

in cui : in which :

nix é un intero compreso tra 0 e 3, preferibilmente 1; nix is an integer between 0 and 3, preferably 1;

m ix é un intero compreso tra l e 3, preferibilmente 1; m ix is an integer comprised between 1 and 3, preferably 1;

uguali o diversi tra loro sono H oppure alchile lineare o ramificato C^-C*; preferibilmente the same or different from each other are H or linear or branched C ^ -C * alkyl; preferably

Y<3 >é un anello eterociclico contenente uno o due atomi di azoto, saturo, insaturo o aromatico, a 5 o 6 atomi, Y <3> is a heterocyclic ring containing one or two nitrogen atoms, saturated, unsaturated or aromatic, with 5 or 6 atoms,

oppure Y può essere·. or Y can be ·.

Y„, scelto tra i seguenti: Y „, chosen from the following:

un gruppo alchilenossi R'O in cui lineare o ramificato quando possibile, avente preferibil-mente da 2 a 6 atomi di carbonio, oppure un cicloalchilene avente da 5 a 7 atomi di carbonio, nell'anello cicloalchilenico uno o più atomi di carbonio possono essere sostituiti da eteroatomi, l'anello può avere catene laterali di tipo R', essendo R' come sopra definito; an alkyleneoxy R'O group in which linear or branched when possible, preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be replaced by heteroatoms, the ring can have side chains of the R 'type, R' being as defined above;

oppure uno dei seguenti gruppi: or one of the following groups:

in cui nf' è un intero da 1 a 6 preferibilmente da 1 a 4; wherein nf 'is an integer from 1 to 6 preferably from 1 to 4;

in cui R1f = H, CH3 e nf ' è un intero da 1 a 6 ; preferibilmente da 1 a 4; wherein R1f = H, CH3 and nf 'is an integer from 1 to 6; preferably from 1 to 4;

oppure Y è ed è scelto tra i seguenti: or Y is and is chosen from the following:

in cui n3 é un intero da 0 a 3 ed n3' é un intero da 1 a 3; wherein n3 is an integer from 0 to 3 and n3 'is an integer from 1 to 3;

in cui n3 ed n3' hanno il significato sopra indicato. in which n3 and n3 'have the meaning indicated above.

Preferibilmente Y<3 >é scelto tra i seguenti: Preferably Y <3> is selected from the following:

Preferibilmente Υ<3 >é un anello aromatico a 6 atomi, contenente un atomo di azoto, detto anello aromatico avente le due valenze libere in posizione 2 e 6. Preferably Υ <3> is an aromatic ring with 6 atoms, containing a nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.

Il preferito di Y<3 >é Y12 (piridile) sostituito in posizione 2 e 6. I legami possono trovarsi anche in posizione non simmetrica, ad esempio Y12 (piridile) può essere sostituito anche in posizione 2 e 3; Yl (pirazolo) può essere 3,5-disostituito. The preferred of Y <3> is Y12 (pyridyl) substituted in position 2 and 6. The bonds can also be found in a non-symmetrical position, for example Y12 (pyridyl) can also be substituted in position 2 and 3; Yl (pyrazole) can be 3,5-disubstituted.

I precursori di Yp, in cui la valenza libera dell'ossigeno é saturata con H e la valenza libera del carbonio terminale é saturata o con un gruppo carbossilico, oppure ossidrilico, sono prodotti reperibili in commercio o possono essere ottenuti con metodi noti nell'arte. The precursors of Yp, in which the free valence of oxygen is saturated with H and the free valence of the terminal carbon is saturated either with a carboxylic or hydroxy group, are products available on the market or can be obtained with methods known in the art. .

I composti precursori di B dei gruppi sopra indicati vengono preparati secondo i metodi noti in letteratura e descritti, ad esempio, nel "The Merck Index", 12a Ed. (1996), qui integralmente incorporato per riferimento. The precursor compounds of B of the groups indicated above are prepared according to the methods known in the literature and described, for example, in "The Merck Index", 12th Ed. (1996), incorporated herein by reference.

I composti di formula (I) preferiti sono i seguenti The preferred compounds of formula (I) are the following

acido 2-(acetilossi)benzoico (4-nitroossi)butil estere (X) 2- (acetyloxy) benzoic acid (4-nitroxy) butyl ester (X)

acido 2- (acetilossi)benzoico 3-(nitroossimetil)fenil estere 2- (acetyloxy) benzoic acid 3- (nitrooxymethyl) phenyl ester

(XI) (XI)

acido 2- (acetilossi)benzoico 4-(nitroossimetil)fenil estere (XII) 2- (acetyloxy) benzoic acid 4- (nitroxymethyl) phenyl ester (XII)

acido 2- (acetilossi)benzoico 2-(nitroossimetil)fenil estere (XIII) 2- (acetyloxy) benzoic acid 2- (nitroxymethyl) phenyl ester (XIII)

acido 2-(acetilossi)benzoico, 2-metossi-4-[(1E)-3-[4-nitroossi butossi]-3-oxo-l-propenil]fenil estere (XIV) 2- (acetyloxy) benzoic acid, 2-methoxy-4 - [(1E) -3- [4-nitroxybutoxy] -3-oxo-1-propenyl] phenyl ester (XIV)

acido 2-(acetilossi)benzoico, 6-(nitroossimetil)-2-metil piridinil estere cloridrato (XV) 2- (acetyloxy) benzoic acid, 6- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XV)

acido 2-idrossi-benzoico, 3-(nitroossimetil)fenil estere (XVI) 2-hydroxy-benzoic acid, 3- (nitroxymethyl) phenyl ester (XVI)

acido 2-(idrossi)benzoico, 4-(nitroossimetil)fenil estere (XVII) 2- (hydroxy) benzoic acid, 4- (nitroxymethyl) phenyl ester (XVII)

acido 2-(idrossi)benzoico, (4-nitroossi)butil estere (XVIII) 2- (hydroxy) benzoic acid, (4-nitroxy) butyl ester (XVIII)

acido 2-(idrossi)benzoico, 2-(nitroossimetil)fenil estere (XIX) 2- (hydroxy) benzoic acid, 2- (nitroxymethyl) phenyl ester (XIX)

acido 2-(idrossi)benzoico, 2-metossi-4-[(1E)-3-[4-nitroossi butossi]-3-oxo-i-propenil]fenil estere (XX) 2- (hydroxy) benzoic acid, 2-methoxy-4 - [(1E) -3- [4-nitroxybutoxy] -3-oxo-i-propenyl] phenyl ester (XX)

(XX) (XX)

N-acetilcisteina, 4-nitroossibutil estere, 2-acetilossi benzoato (XXI) N-acetylcysteine, 4-nitroxybutyl ester, 2-acetyloxy benzoate (XXI)

acido 2-idrossibenzoico, 6-(nitroossimetil)-2-metilpiridinil estere cloridrato (XXII) 2-hydroxybenzoic acid, 6- (nitroxymethyl) -2-methylpyridinyl ester hydrochloride (XXII)

acido 2-idrossibenzoico, 5-(nitroossimetil)-2-metilpiridinil estere cloridrato (XXIII) 2-hydroxybenzoic acid, 5- (nitroxymethyl) -2-methylpyridinyl ester hydrochloride (XXIII)

acido 2-idrossibenzoico, 3-(nitroossimetil)-2-metilpiridinil estere cloridrato (xxiv) 2-hydroxybenzoic acid, 3- (nitroxymethyl) -2-methylpyridinyl ester hydrochloride (xxiv)

acido 2- (acetilossi) benzoico, 5- (nitroossimetil) -2-metil piridinil estere cloridrato (XXV) 2- (acetyloxy) benzoic acid, 5- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXV)

acido 2-idrossibenzoico, 6- (nitroossimetil) -2 -metilpiridinil estere cloridrato (XXVI) 2-hydroxybenzoic acid, 6- (nitroxymethyl) -2 -methylpyridinyl ester hydrochloride (XXVI)

acido 2-idrossibenzoico, 5- (nitroossimetil) -2 -metilpiridinil estere cloridrato (XXVII) 2-hydroxybenzoic acid, 5- (nitroxymethyl) -2 -methylpyridinyl ester hydrochloride (XXVII)

acido 2-idrossibenzoico, 3- (nitroossimetil) -2 -metilpiridinil estere cloridrato (XXVIII) 2-hydroxybenzoic acid, 3- (nitrooxymethyl) -2 -methylpyridinyl ester hydrochloride (XXVIII)

acido 2-(acetilossi)benzoico, 5-(nitroossimetil)-2-metil piridinil estere cloridrato (XXIX) 2- (acetyloxy) benzoic acid, 5- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXIX)

acido 2-(acetilossi)benzoico, 3-(nitroossimetil)-2-metil piridinil estere cloridrato (XXX) 2- (acetyloxy) benzoic acid, 3- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXX)

acido 2-(acetilossi)benzoico, 3-(nitroossimetil)-2-metilpiridinil estere cloridrato (XXXI) 2- (acetyloxy) benzoic acid, 3- (nitroxymethyl) -2-methylpyridinyl ester hydrochloride (XXXI)

I conposti di formula (I) sono ottenibili in generale con metodi noti nell'arte, si vedano ad esempio le domande di brevetto WO 00/61537 quando in formula (I) b0 = c0 = 1, e WO 00/51988 e WO 95/30641 quando b = 0 e c0 = 1, a nome della Richiedente. The compounds of formula (I) are generally obtainable with methods known in the art, see for example the patent applications WO 00/61537 when in formula (I) b0 = c0 = 1, and WO 00/51988 and WO 95 / 30641 when b = 0 and c0 = 1, in the name of the Applicant.

I nitroossi derivati dell'acido salicilico possono essere anche sintetizzati partendo dai corrispondenti nitroossi derivati dell'acido acetilsalicilico, preparato secondo i metodi descritti nelle domande di brevetto sopra menzionate, mediante idrolisi selettiva del gruppo acetilico. Si vedano gli esempi, in particolare l'esempio 15, della domanda di brevetto italiano n. MI2000A 002202 a nome della Richiedente. The nitroxy derivatives of salicylic acid can also be synthesized starting from the corresponding nitroxy derivatives of acetylsalicylic acid, prepared according to the methods described in the aforementioned patent applications, by selective hydrolysis of the acetyl group. See the examples, in particular example 15, of the Italian patent application n. MI2000A 002202 in the name of the Applicant.

Quando i composti di formula (I) utilizzabili nella presente invenzione hanno uno o più centri chirali, essi possono essere in forma racemica o come miscele di diastereoisomeri, come singoli enantiomeri o singoli diastereoisomeri; se presentano asimmetria geometrica si possono utilizzare i composti nella forma cis o trans. When the compounds of formula (I) usable in the present invention have one or more chiral centers, they can be in racemic form or as mixtures of diastereomers, as single enantiomers or single diastereomers; if they show geometric asymmetry, compounds in the cis or trans form can be used.

Quando nella molecola dei composti di formula (I) è presente un gruppo funzionale salificabile, ad esempio un azoto amminico o eterociclico, è possibile utilizzare i sali corrispondenti dei suindicati composti, ottenibili per reazione in solvente organico come ad esempio acetonitrile, tetraidrofurano, con una quantità equimolecolare del corrispondente acido, organico od inorganico. When a salifiable functional group is present in the molecule of the compounds of formula (I), for example an amino or heterocyclic nitrogen, it is possible to use the corresponding salts of the aforementioned compounds, obtainable by reaction in an organic solvent such as for example acetonitrile, tetrahydrofuran, with a equimolecular quantity of the corresponding acid, organic or inorganic.

Esempi di acidi organici utilizzabili sono i seguenti: acido ossalico, tartarico, maleico, succinico, citrico. Examples of usable organic acids are the following: oxalic, tartaric, maleic, succinic, citric acid.

Esempi di acidi inorganici utilizzabili sono i seguenti: acido nitrico, cloridrico, solforico, fosforico. Preferiti sono acido nitrico e cloridrico. Examples of usable inorganic acids are the following: nitric, hydrochloric, sulfuric, phosphoric acid. Preferred are nitric and hydrochloric acid.

Utilizzando i prodotti dell'invenzione viene marcatamente ridotta la vasculopatia ed in particolare il processo di restenosi che può instaurarsi in soggetti sottoposti ad angioplastica, e in particolare in quelli maggiormente a rischio come gli anziani, i diabetici, gli iperlipidemici. Using the products of the invention, vasculopathy is markedly reduced and in particular the restenosis process that can occur in subjects undergoing angioplasty, and in particular in those most at risk such as the elderly, diabetics, hyperlipidemics.

L'uso terapeutico dei prodotti descritti nella presente invenzione risulta vantaggioso, come detto, in quanto questi composti sono in grado di agire sia sul vaso (cellule endoteliali e della muscolatura liscia vasale) sia sulle cellule ematiche (piastrine, leucociti) e fattori ematici. The therapeutic use of the products described in the present invention is advantageous, as mentioned, since these compounds are able to act both on the vessel (endothelial cells and vascular smooth muscle) and on blood cells (platelets, leukocytes) and blood factors.

I conposti di formula (I) sono formulati nelle corrispondenti conposizioni farmaceutiche per uso parenterale, orale secondo le tecniche ben note nel ramo, unitamente agli usuali eccipienti; si veda ad esempio il volume "Remington's Pharmaceutical Sciences" 15a Ed. The compounds of formula (I) are formulated in the corresponding pharmaceutical compositions for parenteral, oral use according to the techniques well known in the art, together with the usual excipients; see for example the volume "Remington's Pharmaceutical Sciences" 15th Ed.

La quantità su base molare del principio attivo in queste formulazioni é uguale o inferiore alla massima posologia indicata per i farmaci precursori. Si possono usare anche dosi superiori data la loro ottima tollerabilità. Le dosi giornaliere dei farmaci precursori si possono trovare nelle pubblicazioni del ramo, come ad esempio nel "Physician's Desk Reference". The quantity on a molar basis of the active principle in these formulations is equal to or lower than the maximum dosage indicated for the precursor drugs. Higher doses can also be used due to their excellent tolerability. The daily doses of precursor drugs can be found in publications in the field, such as in the "Physician's Desk Reference".

I seguenti esenpi illustrano l'invenzione e non sono limitativi dell'ambito della medesima. The following examples illustrate the invention and are not limitative of its scope.

ESEMPIO F1 EXAMPLE F1

Efficacia dell'Aspirina e dell'acido 2-acetil ossibenzoico (3-nitroossimetil)fenil estere (formula XI), in un modello sperimentale di restenosi indotta nel ratto Efficacy of Aspirin and 2-acetyl oxybenzoic acid (3-nitrooxymethyl) phenyl ester (formula XI), in an experimental model of induced restenosis in the rat

L'estere dell'aspirina (NO-Aspirina), è stata sintetizzata come descritto nell'esempio 3 di WO 97/16405. The aspirin ester (NO-Aspirin) was synthesized as described in example 3 of WO 97/16405.

Come confronto è stato utilizzato l'acido 5-benzoil-2,3-diidro-lH-pirrolizin-l-carbossilico (4-nitrossi)butil estere (NO-ketorolac), sintetizzato come descritto nell'esempio 1F di WO 95/30641. As a comparison, the 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid (4-nitroxy) butyl ester (NO-ketorolac) was used, synthesized as described in example 1F of WO 95/30641 .

Ratti Wistar maschi del peso di 300-350 g venivano anestetizzati mediante iniezione intraperitoneale con ketamina (100 mg/kg) e xylazine (5 mg/kg) e sottoposti ad angioplastica secondo la procedura descritta da Indolii el Al., Circulation, 1995, 92, 1230-1235, utilizzando un catetere a palloncino che veniva prima introdotto nell'arco aortico attraverso la carotide destra, poi gonfiato e quindi fatto passare per tre volte avanti e indietro nel lume del vaso. Male Wistar rats weighing 300-350 g were anesthetized by intraperitoneal injection with ketamine (100 mg / kg) and xylazine (5 mg / kg) and subjected to angioplasty according to the procedure described by Indolii el Al., Circulation, 1995, 92 , 1230-1235, using a balloon catheter that was first introduced into the aortic arch through the right carotid, then inflated and then passed back and forth three times into the vessel lumen.

Gli animali venivano divisi in gruppi indicati e sottoposti a trattamento farmacologico come qui sotto descritto per i 14 giorni seguenti il danno vascolare. I prodotti, sciolti in polietilenglicole (PEG 400) sono stati somministrati per via orale mediante sonda gastrica secondo il seguente schema: The animals were divided into indicated groups and subjected to pharmacological treatment as described below for the 14 days following the vascular damage. The products, dissolved in polyethylene glycol (PEG 400), were administered orally by gastric tube according to the following scheme:

2 gruppi ricevevano NO-Aspirina alle dosi di 30 e 100 mg/kg, rispettivamente, 2 groups received NO-Aspirin at doses of 30 and 100 mg / kg, respectively,

2 gruppi ricevevano Aspirina alle dosi di 16 e 54 mg/kg rispettivamente, 2 groups received aspirin at doses of 16 and 54 mg / kg respectively,

l gruppo riceveva NO-Ketorolac alla dose di 10 mg/Kg, l gruppo riceveva Ketorolac alla dose di 5 mg/Kg, il gruppo di controllo riceveva solo il veicolo (PEG 400, 0,2 ml/ratto). The group received NO-Ketorolac at a dose of 10 mg / kg, the group received Ketorolac at a dose of 5 mg / kg, the control group received only the vehicle (PEG 400, 0.2 ml / rat).

Al termine del trattamento gli animali venivano anestetizzati come descritto sopra e le carotidi venivano prima lavate mediante infusione attraverso il ventricolo sinistro di tampone fosfato salino (PBS, pH 7,2, 100ml) poi fissate con PBS contenente paraformaldeide (4%). At the end of the treatment the animals were anesthetized as described above and the carotids were first washed by infusion through the left ventricle of phosphate buffer saline (PBS, pH 7.2, 100ml) then fixed with PBS containing paraformaldehyde (4%).

Gli animali venivano sacrificati e le carotidi rimosse. Per ogni arteria venivano isolate 6 sezioni di 6 μm di spessore. Gli stomaci venivano rimossi e analizzati per valutare i danni alla mucosa gastrica mediante rilevazione delle eventuali lesioni, determinando le rispettive aree delle lesioni sanguinanti e non. The animals were sacrificed and the carotids removed. For each artery, 6 sections of 6 μm thick were isolated. The stomachs were removed and analyzed to assess damage to the gastric mucosa by detecting any lesions, determining the respective areas of bleeding and non-bleeding lesions.

3 delle 6 sezioni di ogni arteria venivano colorate con hematoxylin e eosina per evidenziare i diversi tipi di cellule, le rimanenti 3 sezioni venivano colorate prima con aldehyde fuchsin poi con la soluzione di Gieson per evidenziare la lamina elastica interna (IEL). Le sezioni sono state fotografate e le immagini sono state analizzate attraverso un image analysis System ( Qwin Lite, Leica, Milan) . 3 of the 6 sections of each artery were stained with hematoxylin and eosin to highlight the different types of cells, the remaining 3 sections were stained first with aldehyde fuchsin then with Gieson's solution to highlight the internal elastic lamina (IEL). The sections were photographed and the images were analyzed through an image analysis System (Qwin Lite, Leica, Milan).

Sono stati quindi misurati gli spessori della tonaca media e tonaca neointima e, rispettivamente, della parete dei vasi . I risultati riportati in Tabella l sono espressi come percentuale di restenosi e sono stati calcolati come rapporto tra lo spessore della tonaca neointima e quello della tonaca media (M/N) misurate nelle sezioni dei vari gruppi e ponendo uguale a 100 il rapporto N/M del gruppo di controllo. The thicknesses of the middle and neointima tunic and, respectively, of the vessel wall were then measured. The results reported in Table 1 are expressed as a percentage of restenosis and were calculated as the ratio between the thickness of the neointima tunic and that of the average tunic (M / N) measured in the sections of the various groups and setting the N / M ratio equal to 100. of the control group.

I risultati riportati in Tabella l mostrano che la formazione di neointima nella parete vascolare indotta dalla lesione con il catetere a palloncino viene significativamente ridotta già somministrando basse dosi di NO-aspirina. Invece è necessario somministrare alte dosi di aspirina (confronto), che tuttavia provocano lesioni alla mucosa gastrica, per ottenere una modesta riduzione della restenosi. NO-Ketorolac (confronto) si dimostra poco efficace e dimostra una tossicità gastrica. The results reported in Table 1 show that the formation of neointima in the vascular wall induced by the lesion with the balloon catheter is significantly reduced already by administering low doses of NO-aspirin. Instead it is necessary to administer high doses of aspirin (comparison), which however cause lesions to the gastric mucosa, to obtain a modest reduction in restenosis. NO-Ketorolac (comparison) proves to be ineffective and demonstrates gastric toxicity.

ESEMPIO F2 EXAMPLE F2

Valutazione della mortalità in ratti SP-SHR (stroke-prone spontaneously hypertension rats) trattati con il composto acido 2-acetilossibenzoico (6-nitroossimetil)-2-metilpiridinil estere cloridrato (formula XV), (NO-ASA) e aspirina Assessment of mortality in stroke-prone spontaneously hypertension rats (SP-SHR) treated with the compound 2-acetyloxybenzoic acid (6-nitroxymethyl) -2-methylpyridinyl ester hydrochloride (formula XV), (NO-ASA) and aspirin

Il composto NO-ASA è stato sintetizzato secondo l'esempio 1 della domanda di brevetto WO 00/51988. The NO-ASA compound was synthesized according to example 1 of patent application WO 00/51988.

In questo esperimento sono stati utilizzati ratti SP-SHR che sviluppano una condizione di ipertensione grave e che sono caratterizzati da un'elevata incidenza di infarto cerebrale spontaneo. In questi ratti la patogenesi dell'ischemia cerebrale è predittiva della patologia umana. (Yamori Y. et al. Stroke 1976; 7: 46-53) SP-SHR rats that develop severe hypertension and are characterized by a high incidence of spontaneous cerebral infarction were used in this experiment. In these rats, the pathogenesis of cerebral ischemia is predictive of human pathology. (Yamori Y. et al. Stroke 1976; 7: 46-53)

Tre gruppi composti ciascuno da 12 ratti SP-SHR di 8 settimane di età all'inizio dell'esperimento, ricevevano per 16 settimane con la dieta giornaliera Aspirina (54 mg/kg) NO-ASA (30 mg/kg); il gruppo di controllo riceveva solo la dieta. Three groups each consisting of 12 SP-SHR rats of 8 weeks of age at the start of the experiment, received for 16 weeks with the daily diet Aspirin (54 mg / kg) NO-ASA (30 mg / kg); the control group received only the diet.

Durante il periodo di trattamento cronico è stata valutata la percentuale di sopravvivenza degli animali. The survival rate of the animals was assessed during the chronic treatment period.

I risultati sono riportati in Tabella 2 e mostrano che alla decima settimana tutti gli animali del gruppo di ratti di controllo erano morti, mentre in quello trattato con NO-ASA, anche alla sedicesima settimana non si sono riscontrate morti da infarto cerebrale. The results are reported in Table 2 and show that at the tenth week all the animals of the control group were dead, while in the one treated with NO-ASA, even at the sixteenth week no deaths from cerebral infarction were found.

ESEMPIO F3 EXAMPLE F3

Valutazione del danno vascolare in animali trattati con NO-ASA e Aspirina Evaluation of vascular damage in animals treated with NO-ASA and Aspirin

In questo esperimento sono stati utilizzati ratti SP-SHR come nell'esempio precedente. SP-SHR rats were used in this experiment as in the previous example.

Tre gruppi composti ciascuno da 12 ratti SP-SHR aventi all'inizio dell'esperimento 8 settimane, ricevevano per 6 settimane con la dieta giornaliera Aspirina (54 mg/kg) NO-ASA (30 mg/kg); il gruppo di controllo riceveva solo la dieta. Three groups composed each of 12 SP-SHR rats having 8 weeks at the beginning of the experiment, received for 6 weeks with the daily diet Aspirin (54 mg / kg) NO-ASA (30 mg / kg); the control group received only the diet.

Al termine del trattamento gli animali venivano sacrificati mediante decapitazione e le carotidi venivano isolate. I vasi sono stati aperti e lavati con tampone fosfato sterile (PBS) freddo contenente EDTA (2mM) e conservate in PBS freddo (raffreddato in bagno di ghiaccio) e contenente 2,[6]-ditert-butyl-p-cresolo (50 μΜ), aprotina (0,001%), EDTA (50mM) e chloramphenicol (0,008%). Le arterie sono state fissate con formalina (10%), poi incluse in paraffina e in seguito sezionate. Una parte delle sezioni è stata incubata con anticorpi MDA2, che sono anticorpi diretti contro epitopi specifici per LDL ossidate. At the end of the treatment the animals were sacrificed by decapitation and the carotids were isolated. The jars were opened and washed with cold sterile phosphate buffer (PBS) containing EDTA (2mM) and stored in cold PBS (cooled in an ice bath) and containing 2, [6] -ditert-butyl-p-cresol (50 μΜ ), aprotin (0.001%), EDTA (50mM) and chloramphenicol (0.008%). The arteries were fixed with formalin (10%), then embedded in paraffin and subsequently dissected. A portion of the sections was incubated with MDA2 antibodies, which are antibodies directed against oxidized LDL-specific epitopes.

I risultati ottenuti sono riportati in Tabella 3. I dati sono stati calcolati utilizzando il numero delle sezioni, positive al saggio immunoistochimico con anticorpi MDA2, rilevate nei gruppi di animali trattati e nel gruppo di controllo rispettivamente. I risultati sono espressi come percentuale di riduzione della presenza di LDL (low density lipoprotein) ossidate nella parete vascolare ponendo uguale a 0 il valore misurato nel gruppo di controllo. The results obtained are reported in Table 3. The data were calculated using the number of sections, positive to the immunohistochemical assay with MDA2 antibodies, detected in the groups of animals treated and in the control group respectively. The results are expressed as a percentage reduction in the presence of oxidized LDL (low density lipoprotein) in the vascular wall, setting the value measured in the control group equal to 0.

Un dato di particolare significativo prognostico è quello costituito dal contenuto delle lipoproteine ossidate che sono state trovate essere correlate con la gravità della malattia e l'incidenza della mortalità. A particularly significant prognostic datum is that constituted by the content of oxidized lipoproteins which have been found to be correlated with the severity of the disease and the incidence of mortality.

La riduzione di LDL ossidate è un indice della protezione vasale da danno trombogenico che è causa scatenante dell ' infarto cerebrale . The reduction of oxidized LDL is an index of the vascular protection from thrombogenic damage which is the triggering cause of cerebral infarction.

Tabella 1 Table 1

Tabella 2 Table 2

Tabella 3 Table 3

Claims (6)

RIVENDICAZIONI 1. Uso per la preparazione di farmaci per il trattamento delle vasculopatie di composti, o loro sali, aventi la seguenti formula generale: CLAIMS 1. Use for the preparation of drugs for the treatment of vasculopathies of compounds, or their salts, having the following general formula: in cui: c0 è un intero ed é 0 oppure 1; b0 è un intero ed è 0 oppure 1, con la condizione che c0 e b0 non possono essere contemporaneamente uguali a zero. A = R-C(=0), in cui R é il radicale del farmaco precursore scelto tra l'acido salicico o acetilsalicilico, - in cui TB e TBI sono uguali o diversi; TB = X, dove X = 0, S, NR1C, R1C é H oppure un alchile lineare o ramificato, avente da 1 a 5 atomi di carbonio; TBI = oppure (X)txx, in cui tx e txx hanno il valore di 0 oppure 1; con la condizione che tx = 1 quando txx = 0, tx = 0 quando txx = 1; X é come sopra definito; X2, radicale bivalente, é tale che il corrispondente precursore di in cui la valenza libera di TB è saturata con Z, e quella di TBI con OZ, Z oppure con in cui in which: c0 is an integer and is 0 or 1; b0 is an integer and is 0 or 1, with the proviso that c0 and b0 cannot be equal to zero at the same time. A = R-C (= 0), where R is the radical of the precursor drug selected from salicic or acetylsalicylic acid, - wherein TB and TBI are the same or different; TB = X, where X = 0, S, NR1C, R1C is H or a linear or branched alkyl, having from 1 to 5 carbon atoms; TBI = or (X) txx, where tx and txx have the value of 0 or 1; with the condition that tx = 1 when txx = 0, tx = 0 when txx = 1; X is as defined above; X2, divalent radical, is such that the corresponding precursor of in which the free valence of TB is saturated with Z, and that of TBI with OZ, Z or in which preferibilmente alchile lineare o ramificato quando possibile, uguali o diversi hanno i valori di Z come sopra definito, a seconda che TB e/o oppure X, in funzione dei valori di t, t', tx e txx; il composto precursore di B essendo scelto tra i seguenti: amminoacidi, scelti tra i seguenti: L-carnosina, anserina, selenocisteina, selenometionina, penicilamina, N-acetilpenicilamina, cisteina, N-acetilcistena, glutatione o suoi esteri, preferibilmente estere etilico o isopropilico; idrossiacidi , scelti tra i seguenti: acido gallico, acido ferulico, acido gentisico, acido citrico, acido caffeico, diidrocaffeico, acido p-cumarico, acido vanillico; polialcooli aromatici ed eterociclici, scelti tra i seguenti: acido nordiidroguaiaretico, quercetina, catechina, kaempferolo, sulfuretina, acido ascorbico, acido isoascorbico, idrochinone, gossypol, acido reductico, metossiidrochinone , idrossiidrochinone, propil gallato, saccarosio, 3,5-di-tertbutil-4-idrossibenziltio glicollato, alcool p-cumarico, 4idrossi-feniletilalcool, alcool coniferilico, allopurinolo; composti contenenti almeno una funzione acida libera, scelti tra i seguenti: acido 3,3'-tiodipropionico, acido fumarico, acido diidrossimaleico, acido edetico; C é il radicale bivalente -Tc-Y- in cui Tc = (CO) quando tx = 0, Tc = X quando txx = 0, essendo X come sopra definito; Y é: preferably linear or branched alkyl when possible, the same or different have the values of Z as defined above, depending on whether TB and / o or X, as a function of the values of t, t ', tx and txx; the precursor compound of B being selected from the following: amino acids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicylamine, N-acetylpenicylamine, cysteine, N-acetylcystene, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxy acids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic, p-coumaric acid, vanillic acid; aromatic and heterocyclic polyalcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sulfuretin, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxyhydroquinone, hydroxyhydroquinone, propyl gallate, sucrose-3,5 -4-hydroxybenzylthio glycollate, p-coumaric alcohol, 4-hydroxy-phenylethyl alcohol, coniferyl alcohol, allopurinol; compounds containing at least one free acid function, selected from the following: 3,3'-thiodipropionic acid, fumaric acid, dihydroximalic acid, edetic acid; C is the divalent radical -Tc-Y- in which Tc = (CO) when tx = 0, Tc = X when txx = 0, being X as defined above; Y is: m cui nix é un intero compreso tra 0 e 3, preferibilmente 1; é un intero compreso tra 1 e 3, preferibilmente 1; uguali o diversi tra loro sono H oppure alchile lineare o ramificato preferibilmente sono H. Y<3 >é un anello eterociclico contenente uno o due atomi di azoto, saturo, insaturo o aromatico, a 5 o 6 atomi , oppure Y può essere: Y0, scelto tra i seguenti: un gruppo alchilenossi R'O in cui lineare o ramificato quando possibile, avente preferibilmente da 2 a 6 atomi di carbonio, oppure un cicloalchilene avente da 5 a 7 atomi di carbonio, nell'anello cicloalchilenico uno o più atomi di carbonio possono essere sostituiti da eteroatomi, l'anello può avere catene laterali di tipo R', essendo R' come sopra definito; oppure uno dei seguenti gruppi: m which nix is an integer between 0 and 3, preferably 1; it is an integer comprised between 1 and 3, preferably 1; equal or different from each other are H or linear or branched alkyl preferably are H. Y <3> is a heterocyclic ring containing one or two nitrogen atoms, saturated, unsaturated or aromatic, with 5 or 6 atoms, or Y can be: Y0, chosen from the following: an alkyleneoxy R'O group in which linear or branched when possible, preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be replaced by heteroatoms, the ring can have R 'type side chains, R' being as defined above; or one of the following groups: in cui nf' è un intero da 1 a 6 preferibilmente da 1 a 4; wherein nf 'is an integer from 1 to 6 preferably from 1 to 4; in cui R1f = H, CH3 e nf è un intero da 1 a 6; preferibilmente da 1 a 4; oppure Y è ed è scelto tra i seguenti: wherein R1f = H, CH3 and nf is an integer from 1 to 6; preferably from 1 to 4; or Y is and is chosen from the following: ^ in cui n3 é un intero da 0 a 3 ed n3' é un intero da 1 a 3; ^ wherein n3 is an integer from 0 to 3 and n3 'is an integer from 1 to 3; in cui n3 ed n3' hanno il significato sopra indicato. in which n3 and n3 'have the meaning indicated above. 2. Uso secondo la rivendicazione 1 in cui Y<3 >nella formula (III) é scelto tra i seguenti: Use according to claim 1 wherein Y <3> in formula (III) is selected from the following: 3. Uso secondo la rivendicazione 2, in cui Y é un anello aromatico a 6 atomi, contenente un atomo di azoto e avente le due valenze libere rispettivamente in posizione 2 e 6. Use according to claim 2, wherein Y is a 6-atom aromatic ring, containing a nitrogen atom and having the two free valences in position 2 and 6 respectively. 4. Uso secondo le rivendicazioni 2-3 in cui Y<3 >é Y12 (piridile) sostituito in posizione 2 e 6. Use according to claims 2-3 wherein Y <3> is Y12 (pyridyl) substituted in position 2 and 6. 5. Uso secondo le rivendicazioni 1-4 in cui i composti sono i seguenti: acido 2-(acetilossi)benzoico (4-nitroossi)butil estere (X) 5. Use according to claims 1-4 wherein the compounds are as follows: 2- (acetyloxy) benzoic acid (4-nitroxy) butyl ester (X) acido 2-(acetilossi)benzoico 3-(nitroossimetil)fenil estere (XI ) 2- (acetyloxy) benzoic acid 3- (nitroxymethyl) phenyl ester (XI) acido 2-(acetilossiJbenzoico 4-(nitroossimetil)fenil estere (XII) 2- (acetyloxyJbenzoic acid 4- (nitroxymethyl) phenyl ester (XII) acido 2-(acetilossi)benzoico 2-(nitroossimetil)fenil estere (XIII ) 2- (acetyloxy) benzoic acid 2- (nitroxymethyl) phenyl ester (XIII) acido 2-(acetilossiJbenzoico, 2-metossi-4-[(1E)-3-[4-nitroossi butossi]-3-oxo-l-propenil]fenil estere (XIV) 2- (acetyloxyJbenzoic acid, 2-methoxy-4 - [(1E) -3- [4-nitroxybutoxy] -3-oxo-1-propenyl] phenyl ester (XIV) acido 2-(acetilossi)benzoico, 6-(nitroossimetil)-2 metil piridinil estere cloridrato (XV) 2- (acetyloxy) benzoic acid, 6- (nitroxymethyl) -2 methyl pyridinyl ester hydrochloride (XV) acido 2-idrossi-benzoico, 3 -(nitroossimetil)fenil estere (XVI) 2-hydroxy-benzoic acid, 3 - (nitroxymethyl) phenyl ester (XVI) acido 2 -(idrossi)benzoico, 4-(nitroossimetil)fenil estere (XVII) 2 - (hydroxy) benzoic acid, 4- (nitroxymethyl) phenyl ester (XVII) acido 2-(idrossi)benzoico, (4-nitroossi)butil estere (XVIII) 2- (hydroxy) benzoic acid, (4-nitroxy) butyl ester (XVIII) acido 2-(idrossi)benzoico, 2-(nitroossimetil)fenil estere (XIX) 2- (hydroxy) benzoic acid, 2- (nitroxymethyl) phenyl ester (XIX) acido 2 -(idrossi)benzoico, 2-metossi-4-[(1E)-3-[4-nitroossi butossi]-3-oxo-l-propenil]fenil estere (XX) 2 - (hydroxy) benzoic acid, 2-methoxy-4 - [(1E) -3- [4-nitroxybutoxy] -3-oxo-1-propenyl] phenyl ester (XX) N-acetilcisteina, 4-nitroossibutil estere, 2-acetilossi benzoato (XXI) N-acetylcysteine, 4-nitroxybutyl ester, 2-acetyloxy benzoate (XXI) acido 2-idrossibenzoico, 6-(nitroossimetil)-2-metil piridinil estere cloridrato (XXII) 2-hydroxybenzoic acid, 6- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXII) acido 2-idrossibenzoico, 5-(nitroossimetil)-2-metil piridinil estere cloridrato (XXIII) 2-hydroxybenzoic acid, 5- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXIII) acido 2-idrossibenzoico, 3-(nitroossimetil)-2-metil piridinil estere cloridrato (XXIV) 2-hydroxybenzoic acid, 3- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXIV) acido 2-(acetilossi)benzoico, 5-(nitroossimetil)-2- metilpiridinil estere cloridrato (XXV) 2- (acetyloxy) benzoic acid, 5- (nitroxymethyl) -2- methylpyridinyl ester hydrochloride (XXV) acido 2-idrossibenzoico, 6-(nitroossimetil)-2-metil piridinil estere cloridrato (XXVI) 2-hydroxybenzoic acid, 6- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXVI) acido 2-idrossibenzoico, 5-(nitroossimetil)-2-metil piridinil estere cloridrato (XXVII) 2-hydroxybenzoic acid, 5- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXVII) acido 2-idrossibenzoico, 3-(nitroossimetil)-2-metil piridinil estere cloridrato (XXVIII) 2-hydroxybenzoic acid, 3- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride (XXVIII) acido 2-(acetilossi)benzoico, 5-(nitroossimetil)-2 metilpiridinil estere cloridrato (XXIX) 2- (acetyloxy) benzoic acid, 5- (nitroxymethyl) -2 methylpyridinyl ester hydrochloride (XXIX) acido 2-(acetilossi)benzoico, 3-(nitroossimetil)-2 - metilpiridinil estere cloridrato (XXX) 2- (acetyloxy) benzoic acid, 3- (nitroxymethyl) -2 - methylpyridinyl ester hydrochloride (XXX) acido 2-(acetilossi)benzoico, 3-(nitroossimetil)-2- metilpiridinil estere cloridrato (XXXI) 2- (acetyloxy) benzoic acid, 3- (nitroxymethyl) -2- methylpyridinyl ester hydrochloride (XXXI) 6. Uso secondo le rivendicazioni 1-5 in cui i composti o loro sali vengono impiegati nelle corrispondenti formulazioni farmaceutiche per uso parenterale, orale e topico. 6. Use according to claims 1-5 wherein the compounds or their salts are used in the corresponding pharmaceutical formulations for parenteral, oral and topical use.
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